2021
Mickova, Alena; Kharaishvili, Gvantsa; Kurfurstova, Daniela; Gachechiladze, Mariam; Kral, Milan; Vacek, Ondrej; Pokryvkova, Barbora; Mistrik, Martin; Soucek, Karel; Bouchal, Jan
Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade. Journal Article
In: International journal of molecular sciences, vol. 22, no. 6, 2021, ISSN: 1422-0067, (Place: Switzerland).
Abstract | Links | BibTeX | Tags: *Protein Processing, Androgen/genetics/metabolism, Antigens, Antineoplastic Agents/pharmacology, Cadherins/genetics/metabolism, CD/genetics/metabolism, Cell Line, Cell Survival/drug effects, Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism, Cyclopentanes/pharmacology, Docetaxel/pharmacology, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, multiplex, NEDD8 Protein/*genetics/metabolism, neddylation, Neoplasm Grading, Neoplastic, PC-3 Cells, Post-Translational, Prostate cancer, Prostate/metabolism/pathology, Prostatic Neoplasms/*genetics/metabolism/pathology, Pyrimidines/pharmacology, Receptors, RNA, S-Phase Kinase-Associated Proteins/antagonists & inhibitors/*genetics/metabolism, Skp2 (S-phase kinase-associated protein 2), Slug, Small Interfering/genetics/metabolism, Snail Family Transcription Factors/*genetics/metabolism, Tumor
@article{mickova_skp2_2021,
title = {Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade.},
author = {Alena Mickova and Gvantsa Kharaishvili and Daniela Kurfurstova and Mariam Gachechiladze and Milan Kral and Ondrej Vacek and Barbora Pokryvkova and Martin Mistrik and Karel Soucek and Jan Bouchal},
doi = {10.3390/ijms22062844},
issn = {1422-0067},
year = {2021},
date = {2021-03-01},
journal = {International journal of molecular sciences},
volume = {22},
number = {6},
abstract = {Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.},
note = {Place: Switzerland},
keywords = {*Protein Processing, Androgen/genetics/metabolism, Antigens, Antineoplastic Agents/pharmacology, Cadherins/genetics/metabolism, CD/genetics/metabolism, Cell Line, Cell Survival/drug effects, Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism, Cyclopentanes/pharmacology, Docetaxel/pharmacology, Epithelial-Mesenchymal Transition/genetics, Gene Expression Regulation, Humans, Immunohistochemistry, Lymphatic Metastasis, Male, multiplex, NEDD8 Protein/*genetics/metabolism, neddylation, Neoplasm Grading, Neoplastic, PC-3 Cells, Post-Translational, Prostate cancer, Prostate/metabolism/pathology, Prostatic Neoplasms/*genetics/metabolism/pathology, Pyrimidines/pharmacology, Receptors, RNA, S-Phase Kinase-Associated Proteins/antagonists & inhibitors/*genetics/metabolism, Skp2 (S-phase kinase-associated protein 2), Slug, Small Interfering/genetics/metabolism, Snail Family Transcription Factors/*genetics/metabolism, Tumor},
pubstate = {published},
tppubtype = {article}
}
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.
2017
Samadder, Pounami; Suchánková, Tereza; Hylse, Ondřej; Khirsariya, Prashant; Nikulenkov, Fedor; Drápela, Stanislav; Straková, Nicol; Vaňhara, Petr; Vašíčková, Kateřina; Kolářová, Hana; Binó, Lucia; Bittová, Miroslava; Ovesná, Petra; Kollár, Peter; Fedr, Radek; Ešner, Milan; Jaroš, Josef; Hampl, Aleš; Krejčí, Lumír; Paruch, Kamil; Souček, Karel
In: Molecular cancer therapeutics, vol. 16, no. 9, pp. 1831–1842, 2017, ISSN: 1538-8514 1535-7163, (Place: United States).
Abstract | Links | BibTeX | Tags: Animal, Animals, Antineoplastic Agents/*chemical synthesis/*pharmacology, Apoptosis/drug effects, Biomarkers, Cell Cycle Checkpoints/drug effects, Cell Cycle/drug effects, Cell Line, Checkpoint Kinase 1/*antagonists & inhibitors, Dealkylation/drug effects, Disease Models, Dose-Response Relationship, Drug, Drug resistance, Humans, Methylation, Mice, Molecular Structure, Neoplasm/*drug effects, Protein Kinase Inhibitors/*chemical synthesis/*pharmacology, Pyrazoles/pharmacology, Pyrimidines/pharmacology, Tumor, Xenograft Model Antitumor Assays
@article{samadder_synthesis_2017,
title = {Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation.},
author = {Pounami Samadder and Tereza Suchánková and Ondřej Hylse and Prashant Khirsariya and Fedor Nikulenkov and Stanislav Drápela and Nicol Straková and Petr Vaňhara and Kateřina Vašíčková and Hana Kolářová and Lucia Binó and Miroslava Bittová and Petra Ovesná and Peter Kollár and Radek Fedr and Milan Ešner and Josef Jaroš and Aleš Hampl and Lumír Krejčí and Kamil Paruch and Karel Souček},
doi = {10.1158/1535-7163.MCT-17-0018},
issn = {1538-8514 1535-7163},
year = {2017},
date = {2017-09-01},
journal = {Molecular cancer therapeutics},
volume = {16},
number = {9},
pages = {1831–1842},
abstract = {Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G(2)-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. ©2017 AACR.},
note = {Place: United States},
keywords = {Animal, Animals, Antineoplastic Agents/*chemical synthesis/*pharmacology, Apoptosis/drug effects, Biomarkers, Cell Cycle Checkpoints/drug effects, Cell Cycle/drug effects, Cell Line, Checkpoint Kinase 1/*antagonists & inhibitors, Dealkylation/drug effects, Disease Models, Dose-Response Relationship, Drug, Drug resistance, Humans, Methylation, Mice, Molecular Structure, Neoplasm/*drug effects, Protein Kinase Inhibitors/*chemical synthesis/*pharmacology, Pyrazoles/pharmacology, Pyrimidines/pharmacology, Tumor, Xenograft Model Antitumor Assays},
pubstate = {published},
tppubtype = {article}
}
Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G(2)-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. ©2017 AACR.